This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypotheses: Early aggressive therapy of aggressive Rheumatoid Arthritis (RA) will achieve greater therapeutic responses both early on and at later time points. Treatment with methotrexate (MTX) plus a biologic agent will have a superior response to MTX plus two other small molecule DMARDs [etanercept or SSZ (sulfasalazine) plus HCQ (hydroxychloroquine)]. Objectives: Patients with early (3yrs) aggressive disease (2 erosions and active disease) will be randomized to one of four therapeutic arms: 1) MTX + etanercept; 2) MTX + SSZ/HCQ; 3) MTX alone for 6 months and if inadequate response add etanercept or placebo; 4) MTX alone for 6 months and if inadequate response add SSZ/HCQ. The primary endpoint is the area under the curve of the DAS28, a composite measure of RA activity that has been used in a number of trials and that correlates well with other composite measures. Other endpoints include a long list of radiological and clinical endpoints that are generally well accepted. Other than MTX, this is a placebo-controlled trial that is multicenter, with central control at the University of Alabama. Significance: The paradigm for treating RA has been undergoing rapid change over the past few years with the development of new agents for the treatment of RA that are efficacious and that appear to have little added toxicity as compared to older agents. Although it is clear that addition of a biologic or multiple small molecule agents is useful for patients with established resistant RA, the approach to therapy of early aggressive RA is less well established. This trial should help establish the best approach to therapy in patients with early RA. Approach: The design of this protocol is a 'real-world' blinded, placebo-controlled trial of multiple approaches to therapy. The arms are sufficiently well defined as to yield interpretable results that will go a long way towards establishing the appropriate approach to treating patients with recent onset aggressive
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